Method for fabricating a stent with nucleating agent

ABSTRACT

The use of nucleating agents to manufacture polymeric stents is disclosed. The resulting stents may have increased crystallinity, decreased crystal size, increased mechanical properties, and faster degradation times.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of using nucleating agents in stentmanufacturing.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a retractable sheath or a sock. Whenthe stent is in a desired bodily location, the sheath may be withdrawnwhich allows the stent to self-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as, hoop or circumferential strengthand rigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. Generally, it is desirable to minimize recoil.

In addition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Longitudinal flexibility isimportant to allow the stent to be maneuvered through a tortuousvascular path and to enable it to conform to a deployment site that maynot be linear or may be subject to flexure. Finally, the stent must bebiocompatible so as not to trigger any adverse vascular responses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, fibers, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.

Furthermore, it may be desirable for a stent to be biodegradable. Inmany treatment applications, the presence of a stent in a body may benecessary for a limited period of time until its intended function of,for example, maintaining vascular patency and/or drug delivery isaccomplished. Therefore, stents fabricated from biodegradable,bioabsorbable, and/or bioerodable materials such as bioabsorbablepolymers should be configured to completely erode only after theclinical need for them has ended.

There are several characteristics that are important for implantablemedical devices, such as stents, including high radial strength and goodfracture toughness. Some crystalline or semi-crystalline polymers thatmay be suitable for use in implantable medical devices have potentialshortcomings with respect to some of these characteristics, inparticular, fracture toughness.

Current polylactide or poly(lactic acid) (PLA) stents have slowdegradation times (about 3 years or more). Substitutions such as the useof poly(glycolide-co-lactide) or poly(glycolic acid-co-lactic acid)(PLGA) materials have been made in the past to shorten the degradationrate. However, this resulted in deteriorated mechanical properties andstability of the formed stent due to low crystallinity and lowcrystallization rate. Thus, there is a need for a faster degrading PLGAstent without sacrificing mechanical properties or stability.

SUMMARY OF THE INVENTION

Several embodiments of the present invention are directed to a method offabricating a polymeric stent including combining a polymer such as PLGAwith a nucleating agent to form a polymer mixture, forming polymertubing from the polymer mixture, and fabricating the stent from thetubing. The nucleating agent is used to increase the crystallinity anddecrease the crystal size of the polymer tubing.

In certain embodiments, the nucleating agent includes polyglycolide(PGA), poly(glycolide-co-lactide) (PGLA) with small amount or lactide(less than 10%), inorganic compounds, or organic compounds.

Some embodiments are directed to a method of fabricating a polymericstent including combining PLGA with a nucleating agent to form a polymermixture, forming polymer tubing from the polymer mixture, stressinducing crystallization, and fabricating the stent from the tubing. Thenucleating agent and the stress inducing step increase the crystallinityof the polymer tubing as the tubing is extruded and during the stressinducing step. The blending of the polymer and the nucleating agent maybe accomplished using mechanical blending, melt blending, solutionblending, or combinations thereof.

In an embodiment, the tubing extrusion step is immediately followed by adeformation step. In other embodiments, after the tubing has beenextruded, the tubing is cooled and then reheated for the stress inducingstep.

In several embodiments, the stress inducing crystallization stepincludes deformation of the polymer tubing radially, axially, or both.In some embodiments, blow molding is used to deform the polymer tubing.

Some embodiments of the invention are directed to a polymeric stentcomprising PLGA with PGA added as a nucleating agent.

Other embodiments are directed to a polymeric stent where PLGA and anucleating agent are blended together, wherein the nucleating agent isan inorganic or organic compound.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIGS. 2A, B depict a portion of the stent in FIG. 1 without a nucleatingagent.

FIGS. 3A, B depict a portion of the stent in FIG. 1 including anucleating agent.

FIG. 4 depicts the degradation rates of a PGA and PLA polymers.

FIG. 5 depicts an axial cross-section of a polymer tube positionedwithin an annular member or mold.

FIG. 6 depicts a deformed polymeric tube in a mold.

FIG. 7 depicts a schematic plot of the crystal nucleation rate and thecrystal growth rate, and the overall rate of crystallization.

DETAILED DESCRIPTION OF THE INVENTION

The various embodiments of the present invention relate to a polymerstent composition and methods of fabricating a polymeric stent that havegood or optimal toughness and selected mechanical properties along theaxial direction or circumferential direction of the stent, or both. Thepresent invention can be applied to devices including, but is notlimited to, self-expandable stents, and balloon-expandable stents.

For the purposes of the present invention, the following terms anddefinitions apply:

The “glass transition temperature,” T_(g), is the temperature at whichthe amorphous domains of a polymer change from a brittle, vitreous stateto a solid, deformable or ductile state at atmospheric pressure. Inother words, the T_(g) corresponds to the temperature where the onset ofsegmental motion in the chains of the polymer occurs. When an amorphousor semicrystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is raised the actual molecular volume in thesample remains constant, and so a higher coefficient of expansion pointsto an increase in free volume associated with the system and thereforeincreased freedom for the molecules to move. The increasing heatcapacity corresponds to an increase in heat dissipation throughmovement. T_(g) of a given polymer can be dependent on the heating rateand can be influenced by the thermal history of the polymer.Furthermore, the chemical structure of the polymer heavily influencesthe glass transition by affecting mobility.

“Stress” refers to force per unit area, as in the force acting through asmall area within a plane. Stress can be divided into components, normaland parallel to the plane, called normal stress and shear stress,respectively. Tensile stress, for example, is a normal component ofstress applied that leads to expansion (increase in length). Inaddition, compressive stress is a normal component of stress applied tomaterials resulting in their compaction (decrease in length). Stress mayresult in deformation of a material, which refers to a change in length.“Expansion” or “compression” may be defined as the increase or decreasein length of a sample of material when the sample is subjected tostress.

“Strain” refers to the amount of expansion or compression that occurs ina material at a given stress or load. Strain may be expressed as afraction or percentage of the original length, i.e., the change inlength divided by the original length. Strain, therefore, is positivefor expansion and negative for compression.

“Modulus” may be defined as the ratio of a component of stress or forceper unit area applied to a material divided by the strain along an axisof applied force that results from the applied force. For example, amaterial has both a tensile and a compressive modulus.

“Solvent” is defined as a substance capable of dissolving or dispersingone or more other substances or capable of at least partially dissolvingor dispersing the substance(s) to form a uniformly dispersed mixture atthe molecular- or ionic-size level. The solvent should be capable ofdissolving at least 0.1 mg of the polymer in 1 ml of the solvent, andmore narrowly 0.5 mg in 1 ml at ambient temperature and ambientpressure.

“Non-solvent” is defined as a substance incapable of dissolving theother substance. The non-solvent should be capable of dissolving onlyless than 0.1 mg of the polymer in 1 ml of the non-solvent at ambienttemperature and ambient pressure, and more narrowly only less than 0.05mg in 1 ml at ambient temperature and ambient pressure.

“Percent crystallinity” refers to the percentage of the polymer materialthat is in a crystalline form. It is thought that the methods of thepresent invention can increase the percent crystallinity of the polymer.

Those of ordinary skill in the art understand that there are severalmethods for determining the percent crystallinity in polymers. Thesemethods are, for example, described in L. H. Sperline, Introduction toPhysical Polymer Science (3rd ed. 2001). The first involves thedetermination of the heat of fusion of the whole sample by calorimetricmethods. The heat of fusion per mole of crystalline material can then beestimated independently by melting point depression experiments. Thepercent crystallinity is then given by heat of fusion of the wholesample divided by the heat of fusion per mole of crystalline materialtimes 100. Representative example of this process and calculation aredescribed in Sarasua et al., Crystallization and Melting Behavior ofPolylactides, Macromolecules 31(12), 3895-3905 (1998); and Reeve et al.,Polylactide Stereochemistry: Effect of Enzymatic Degradability,Macromolecules 27(3), 825-31 (1994) (citing Bloembergen et al., Studiesof Composition and Crystallinity of BacterialPoly(β-hydroxybutyrate-co-β-hydroxyvalerate, Macromolecules 19(11),2865-70 (1986)).

A second method stems from the fact that X-ray diffraction depends onthe number of electrons involved and is thus proportional to thedensity. Besides Bragg diffraction lines for the crystalline portion,there is an amorphous halo caused by the amorphous portion of thepolymer. The amorphous halo occurs at a slightly smaller angle than thecorresponding crystalline peak, because the atomic spacings are larger.The amorphous halo is broader than the corresponding crystalline peak,because of the molecular disorder. This second method can be quantifiedby the crystallinity index, CI, where

${C\; I} = \frac{Ac}{{Aa} + {Ac}}$

and where Ac and Aa represent the area under the Bragg diffraction lineand corresponding amorphous halo, respectively.

A stent may include a pattern or network of interconnecting structuralelements or struts. FIG. 1 depicts an example of a three-dimensionalview of a stent 10. The stent may have a pattern that includes a numberof interconnecting elements or struts 15. The embodiments disclosedherein are not limited to stents or to the stent pattern illustrated inFIG. 1. The structural pattern of the device can be of virtually anydesign, The variations in the structure of patterns are virtuallyunlimited. As shown in FIG. 1 the geometry or shape of stents varythroughout its structure. A pattern may include portions of struts thatare straight or relatively straight, an example being a section 20.Patterns may also include intersections of struts with curved or bentportions or elements as in sections 25 and 30. In addition, patterns mayinclude struts that include curved or bent portions or elements as in asection 35.

Additionally, a surface of a medical device, such as a stent, may alsobe characterized by the relative location of the surface with respect toa bodily lumen. The stent includes abluminal surfaces or outer portions,luminal surfaces or inner portions, and surfaces between the abluminaland luminal surfaces. For example, struts 15 of stent 10 include luminalfaces or surfaces 40, abluminal faces or surfaces 45, and side-wallfaces or surfaces 50.

A stent such as stent 10 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form the tube. A tube or sheetcan be formed by extrusion or injection molding. A stent pattern, suchas the one pictured in FIG. 1, can be formed in a tube or sheet with atechnique such as laser cutting or chemical etching. Representativeexamples of lasers that may be used include, but are not limited to,excimer, carbon dioxide, and YAG. The stent can then be crimped on to aballoon or catheter for delivery into a bodily lumen.

The underlying structure or substrate of a stent can be completely or atleast in part made from a biodegradable polymer or combination ofbiodegradable polymers, a biostable polymer or combination of biostablepolymers, or a combination of biodegradable and biostable polymers.Additionally, a polymer-based coating for a surface of a device can be abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers.

There are several mechanical properties that are important for a stent.These include high radial strength, adequate toughness, low recoil, andresistance to physical aging. A stent must have adequate strength,particularly, in the radial direction to withstand structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Radial strength is associated with strength ofthe stent around the circumferential direction of the stent. Inaddition, the stent must possess sufficient toughness so that the stentexhibits sufficient flexibility to allow for crimping, expansion, andflexure. A stent should have sufficient toughness so that it isresistant to crack formation, particularly, in high strain regions.Recoil refers to the retraction of a stent radially inward from itsdeployed diameter.

A stent can be made in whole or in part of a biodegradable polymer. Abiodegradable stent can be configured to erode from an implant site whenit is no longer needed. A biodegradable stent allows further surgery orintervention, if necessary, on a treated vessel and reduces thelikelihood of late stent thrombosis, a condition in which clots form onthe surface of the stent months or years after deployment. Somecrystalline or semi-crystalline biodegradable polymers that are glassyor have a glass transition temperature (Tg) above body temperature areparticularly attractive as stent materials due to their strength andstiffness at physiological conditions. Such glassy polymers can beabsorbed through chemical degradation, such as hydrolysis. Physiologicalconditions refer to conditions that an implant is exposed to within ahuman body. Physiological conditions include, but are limited to, humanbody temperature, approximately 37° C.

However, the mechanical properties of such polymers may requireimprovement to be suitable as stent materials. For example, the strutsof stent may have to be undesirably large to have radial strengthsufficient to support the walls of a vessel. Therefore, the strength ofsuch polymers may need improvement. Additionally, the toughness of suchpolymers can be lower than desired, in particular, for use in stentapplications. For example, polymers such as poly(L-lactide) (PLLA) arestiff and strong, but tend to be brittle under physiological conditions.These polymers can exhibit a brittle fracture mechanism at physiologicalconditions in which there is little or no plastic deformation prior tofailure. A stent fabricated from such polymers can have insufficienttoughness for the range of use of a stent. As a result, cracks,particularly in high strain regions, can be induced, which can result inmechanical failure of the stent.

Furthermore, recoil can result from creep and stress relaxation whichresult from relaxation or rearrangement of polymer chains. Creep refersto the gradual deformation that occurs in a polymeric constructsubjected to an applied load. Stress relaxation occurs when deformation(or strain) is constant and is manifested by a reduction in the force(stress) required to maintain a constant deformation

Physical aging can also be a problem with such semicrystalline polymers.Physical aging, as used herein, refers to densification in the amorphousregions of a semi-crystalline polymer. Densification is the increase indensity of a material or region of a material and results fromreordering of polymer chains. Densification tends to decrease thefracture toughness of a polymer.

In general, the mechanical properties of a polymer depend upon itsmorphology or microstructure. Various embodiments of the presentinvention include processing a polymeric construct that is a precursorto a stent to obtain desirable or selected mechanical properties of thestent. Such desirable or selected mechanical properties can correspondto a particular structure or morphology. Embodiments of the presentinvention include adjusting the processing conditions to obtain selectedor desirable properties.

Morphology includes crystallinity, molecular orientation of polymerchains, and crystal size. A polymer may be completely amorphous,partially crystalline, or almost completely crystalline. A partiallycrystalline polymer includes crystalline regions separated by amorphousregions. The degree of crystallinity is the sum of all the crystallineregions. Molecular orientation refers to the relative orientation ofpolymer chains along a longitudinal or covalent axis of the polymerchains. The orientation can refer to both the orientation of polymerchains the crystalline regions and the amorphous regions.

The relationship between the morphology and mechanical properties can beof use in alleviating some of the shortcomings of the semi-crystallinepolymers mentioned above. In general, the modulus of a polymer increasesas crystallinity increases. As mentioned above, a semi-crystallinepolymer with a high degree of crystallinity can be brittle and issusceptible to cracking. An amorphous polymer may be more flexible orductile, but may have insufficient radial strength. Additionally, thesize of crystalline regions in a polymer can affect mechanicalproperties. It is believed that decreasing the size of crystallineregions or domains while maintaining a degree of crystallinity in apolymer increases the fracture toughness of the polymer.

FIGS. 2A, B depict a blown up view of a portion 35 of a strut 10 (shownin FIG. 1) with area 200 that has been deformed without the use of anucleating agent. The crystalline domains 210 dispersed in amorphousdomain 220 are less numerous as compared to FIG. 3B, where portion 300has a greater number of smaller crystalline domains 310 dispersed inamorphous domain 320.

FIGS. 3A, B depict a blown up view of a portion of 35 of strut 10 witharea 300 that has been deformed where the polymer has been blended witha nucleating agent. The crystalline domains 310 are more numerous, andare smaller in size. The size of the crystals is also smaller.

Small crystalline domains 310 serve as net-points to constrain polymerchains in the amorphous domain 320 of portion 300. The motion of thepolymer chains is restricted through the high number of smallcrystalline domains 310.

As mentioned above, current PLLA stents have degradation times of about3 years or more. Poly(lactide-co-glycolide) (PLGA) polymeric materialwith less than about 25 wt % glycolide (GA) may be used to replace PLLAas a stent polymer material to accelerate the degradation rate. In someembodiments, the wt % of GA is from 5 wt % to 15 wt %. However, PLGA hasa slow crystallization rate and low crystallinity. For PLGA, the GAcontent may be manipulated to change the degradation time. FIG. 4graphically shows how the degradation rate changes with the amount of GAin the polymer. If the GA content is increased from about 5 wt % toabout 15 wt %, then the degradation time is expected to change fromabout 28 months to about 18 months. However, as the GA content in thePLGA increases, the crystallization rate and crystallinity of theresulting polymer decrease, which would deteriorate the mechanicalproperties and stability of a formed stent.

The embodiments below use PLGA for the polymer portion of thepolymer/nucleating agent blend. However, other useful polymers for thepolymer portion are PLA, poly(lactide-co-caprolactone)(PLA-PCL),poly(lactide-co-trimethylene carbonatc)(PLA-PTMC), andpoly(lactide-co-p-dioxanone)(PLA-PDO).

In several embodiments of the present invention, the crystallinity andcrystallization rate of a PLGA polymer may be increased by adding anucleating agent. The nucleating agent can be a fast crystallizingpolymer, or a crystallizing organic or inorganic compound. To form thepolymer/nucleating agent mixture, mechanical blending, melt blending,solution blending, or combinations thereof may be used. Mechanicalblending may be accomplished by using a mechanical blender. A twin screwextruder may be used for melt blending. Solution blending may beaccomplished by dissolving both the polymer and nucleating agent in aco-solvent and then precipitating them in a non-solvent.

In one embodiment, the polymeric nucleating agent is polyglycolide orpoly(glycolic acid) (PGA) and is combined with PLGA. In certainembodiments, PGA and PLGA are combined using melt extrusion. In severalembodiments the amount of nucleating agent is about 0.1 to about 10% byweight. In certain embodiments, the amount of nucleating agent is about0.2 to about 5% by weight. PGA would form a small crystalline structurefirst, and these small crystals would increase nucleation density andaccelerate the entire crystallization rate of the PLGA matrix material.PGA alone has a fast degradation rate (typically less than one year todegrade), and its degradation product and micro-pore structure createdby the degradation of PGA would accelerate the degradation of the PLGAmatrix. Upon manufacturing a stent using the nucleated matrix, the stentwould posses both improved mechanical properties and a fasterdegradation rate.

In an embodiment, for the PLGA, the LLA:GA ratio is in the range ofabout 80:20 to 99.99:0.01, or about 85:15 to about 95:5. As the GAcontent increases in the PLGA, then the crystallization rate andcrystallinity may decrease, which leads to reduced stability. In certainembodiments, the nucleating agent is 0.1 to 10 wt %, 0.2 to 5 wt %, or 5wt % PGA and is blended with PLGA (LLA:GA=90:10) to form a polymermixture with increased crystallinity or decreased crystal size.

In another embodiment, the polymeric nucleating agent ispoly(lactide-co-glycolide) (PGLA) with less than about 10 wt %L-lactide, and the PGLA is combined with PLGA. In certain embodimentsthe amount of nucleating agent is about 0.1 to about 10% by weight. Insome embodiments, the amount of nucleating agent is about 0.2 to about5% by weight. PGLA has a faster crystallization rate than the PLGA andalso a faster degradation rate than the PGA mentioned above. When PGLAis used instead of PGA as a nucleating agent, a PLGA stent containingthe PGLA nucleating agent would possess an even faster degradation ratethan a stent using PGA as a nucleating agent.

In an embodiment, in the PLGA, the LLA:GA ratio is about 80:20 to about99.99:0.01, or about 85:15 to about 95:5. For the nucleating agent, PGLAcan be used where the GA:LLA ratio is about 90:10 to about 99.99:0.01,or about 95:5 to about 99:1. In certain embodiments, the nucleatingagent is 5 wt % PGLA (GA:LLA=98:2) and is blended with PLGA(LLA:GA=90:10) to form a polymer mixture with increased crystallinity.

In several embodiments, the nucleating agent is an organic or inorganiccompound. Organic or inorganic nucleating agents may include, but arenot limited to, nano Mg silicate hydrate, ethylene bis(1,2-hydroxystearylamide), boron nitride, hydroxyapatite,decamethylenedicarboxylichydrazide, dibenzoylhydrazide, dioctylphthalate, citric acid esters, lactic acid esters, lactide esters, ethyllactate, triphenyl phosphate, glycerine, acetin, and butyrin. In certainembodiments the amount of nucleating agent is about 0.1 to about 10% byweight. In some embodiments, the amount of nucleating agent is about 0.2to about 5% by weight. With respect to organic or inorganic compounds,nano particles may provide improved radial strength and toughness. Anyof the above listed compounds can be in the form of nano particles, forexample Mg silicate hydrate with a size of 10 nm to 500 nm.

In an embodiment using the organic or inorganic nucleating agents above,for the PLGA, the LLA:GA ratio is in the range of about 80:20 to about99.99:0.01, or about 85:15 to about 95:5. In certain embodiments, thenucleating agent is 1 wt % nano magnesium silicate hydrate and isblended with PLGA (LLA:GA ratio=90:10) to form a polymer mixture withincreased crystallinity and decreased crystal size.

For the blending of the PLGA with a nucleating agent, conventional meltcompounding into a PLGA matrix using melt compounding equipment may beused. Examples of melt compounding equipment includes, but is notlimited to, single and twin screw extruders, roll mills, Banbury mixers,and Farrell continuous mixers. In certain embodiments, the nucleatingagent may be added during the PLGA tubing extrusion process through aseparate feeding window.

A further embodiment of combining the PLGA and the nucleating agent isthrough solution blending. PLGA and the nucleating agent are bothdissolved in a co-solvent and then precipitated in a non-solvent. Theresulting mixture may then be used to form tubing using one of theextrusion methods mentioned above. Examples of co-solvents include, butare not limited to, chloroform, ethylene dichloride, tetrahydrofuran(THF), and combinations thereof. Examples of non-solvents include, butare not limited to, methanol, ethanol, isopropanol, pentane, hexane, andcombinations thereof.

The PLGA/nucleating agent compositions discussed above may be used inthe manufacturing/deforming procedures discussed below.

The strength and toughness of the polymer including the nucleating agentcan be affected by the orientation of polymer chains. The toughness of asemi-crystalline polymer can be increased by inducing orientation ofpolymer chains in both the crystalline and amorphous regions. Inaddition, the strength of the polymer is also increased along thedirection of preferred orientation.

It is believed that crystalline domains can act as net points to tiepolymer chains in the amorphous regions between the domains. Smallerdomains at a given degree of crystallinity result in a greater number ofdomains and tie molecules, resulting in increased toughness. Thestrength and toughness of the amorphous regions can be further beincreased by inducing orientation in the amorphous regions. It isexpected that a higher number of net points and tie molecules withinduced orientation can lead to higher strength and fracture toughness.

Certain embodiments of the present invention include processing a stentprecursor construct, such as a polymer tube with the polymeric materialincluding a nucleating agent, to modify the morphology of the polymer inthe construct so that the construct has desired or selected properties.It is well known by those skilled in the art that the mechanicalproperties of a polymer can be modified by applying stress to a polymer.James L. White and Joseph E. Spruiell, Polymer and Engineering Science,1981, Vol. 21, No. 13. The application of stress can induce molecularorientation along the direction of stress which can modify mechanicalproperties along the direction of applied stress. Induced orientation inconstructs such as polymer tubes can be particularly useful since tubesformed by extrusion tend to possess no or substantially no polymer chainalignment in the circumferential direction. A tube made from injectionmolding has a relatively low degree of polymer chain alignment in boththe axial and circumferential directions.

Molecular orientation can be induced in polymers that are completelyamorphous, partially or semi-crystalline, or almost completelycrystalline. A partially or semi-crystalline polymer includescrystalline regions separated by amorphous regions. The crystallineregions do not necessarily have the same or similar orientation ofpolymer chains. However, a high degree of orientation of crystallitesmay be induced by applying stress to a semi-crystalline polymer. Thestress may also induce orientation in the amorphous regions.

Due to the magnitude and directions of stresses imposed on a stentduring use, it is important for the mechanical stability of a device tohave an adequate magnitude of strength both in axial and circumferentialdirections. Therefore, an adequate balance of axial and circumferentialstrength is also important for mechanical stability. The relative amountof axial and circumferential orientation may depend on a number offactors such as the stent pattern, initial diameter of the tube, finaldiameter of the stent, and crimped diameter of the stent. Polymer tubesformed by extrusion methods, such as those with polymeric materialsincluding nucleating agents, tend to possess a significant degree ofaxial polymer chain alignment. However, such conventionally extrudedtubes tend to possess no or substantially no polymer chain alignment inthe circumferential direction.

Some embodiments of a method of fabricating a stent may include radiallydeforming a polymeric tube about a cylindrical axis of the tube, whereinthe polymeric material contains a nucleating agent. The tube can beradially deformed to increase the strength and modulus in thecircumferential direction. The increase in strength and modulus can bedue to the induced molecular orientation in the circumferentialdirection.

Additionally, the method may further include axially deforming thepolymeric tube along the cylindrical axis of the tube. In oneembodiment, the tube may be axially deformed by applying a tensile forceto the tube along the cylindrical axis. Axial deformation of the polymertube may induce axial molecular orientation, and hence, increase theaxial strength and modulus or rigidity. Various embodiments may includeradially deforming the tube prior to, subsequent to, and/orcontemporaneously with axial deformation the tube.

The degree of polymer chain alignment induced with applied stress maydepend upon the temperature of the polymer. Above Tg, polymer chainalignment may be readily induced with applied stress since polymerchains have greater mobility than below Tg. Consequently, the amount ofdeformation depends on the temperature of a polymeric material.Therefore, it is advantageous to radially deform the tube at atemperature above Tg.

Additionally, the polymeric tube including a nucleating agent may beheat set to allow polymeric chains to rearrange upon deformation. “Heatsetting,” as used herein, refers to maintaining a polymer at an elevatedtemperature to allow polymer chains in the heated polymer to move towarda state of thermodynamic equilibrium. In a deformed polymeric tube wherethe polymeric material includes a nucleating agent, polymeric chains areallowed to equilibrate towards the induced highly oriented structure atthe elevated temperature. Since polymer chain alignment is a time andtemperature dependent process, a highly oriented structure that isthermodynamically stable at a given temperature may not be formedinstantaneously. Thus, the polymeric tube may be maintained in adeformed state at an elevated temperature for a period of time.

A tube made of a polymeric material including a nucleating agent can beradially deformed using blow molding. FIGS. 5 and 6 illustrate anembodiment of deforming a polymeric tube in manufacturing a stent. FIG.5 depicts an axial cross-section of a polymeric tube 150 with an outsidediameter 155 positioned within an annular member or mold 160. Mold 160may act to limit the radial deformation of polymeric tube 150 to adiameter 165, the inside diameter of mold 160. Polymer tube 150 may beclosed at a distal end 170. Distal end 170 may be open in subsequentmanufacturing steps. A fluid may be conveyed, as indicated by an arrow175, into an open proximal end 180 of polymeric tube 150. A tensileforce 195 is applied at proximal end 180 and a distal end 170.

Polymeric tube 150 may be heated by heating the gas to a temperatureabove ambient temperature prior to conveying the gas into polymeric tube150. Alternatively, the polymeric tube may be heated by heating theexterior of mold 160. The tube may also be heated by the mold. Theincrease in pressure inside of polymer tube 150 facilitated by anincrease in temperature of the polymeric tube causes radial deformationof polymer tube 150, as indicated by an arrow 185. FIG. 6 depictspolymeric tube 150 in a deformed state with an outside diameter 190within annular member 160.

Additionally, as indicated above, the pressure inside the tube and thetemperature of the tube may be maintained at the elevated temperaturefor a period of time to allow the polymeric tube to be heat set. Theperiod of time may be between about one minute and about two hours, ormore narrowly, between about two minutes and about ten minutes.

Furthermore, the tube may be expanded to a target diameter. In oneembodiment, the target diameter may be the diameter at which a stentpattern is formed by laser machining the tube. The target diameter canalso correspond to the diameter of a stent prior to crimping. The degreeof radial deformation may be quantified by a blow-up ratio or radialdraw ratio:

$\frac{{Inside}\mspace{14mu}{Diameter}\mspace{14mu}{of}\mspace{14mu}{Deformed}\mspace{14mu}{Tube}}{{Original}\mspace{14mu}{Inside}\mspace{14mu}{Diameter}\mspace{14mu}{of}\mspace{14mu}{Tube}}$In some embodiments, the radial draw ratio of a polymeric tube for usein fabricating a stent may be between about 1 and 20, or more narrowlybetween about 2 and 6. Similarly, the degree of axial deformation may bequantified by an axial draw ratio:

$\frac{{Length}\mspace{14mu}{of}\mspace{14mu}{Deformed}\mspace{14mu}{Tube}}{{Original}\mspace{14mu}{Length}\mspace{14mu}{of}\mspace{14mu}{Tube}}$

In some embodiments, a stent can be fabricated from the radiallyexpanded tube by laser machining. The stent may then be crimped on to adelivery device such as a balloon. Therefore, the extruded tube musthave a diameter that is less than a target diameter, the target diametercorresponding to a diameter at which a stent pattern is formed by lasermachining or a diameter of a stent prior to crimping. Thus, the extrudedtube can then be radially expanded to the target diameter.

The degree of induced strength due to radial expansion depends on theamount of radial expansion as quantified by the blow-up ratio. Thus, thedegree of radial expansion is determined by the extruded diameter andthe target diameter. In some embodiments, the extruded diameter can beused to determine the degree of radial expansion. The smaller theextruded diameter, the larger is the degree of radial expansion. In someembodiments, the extruded diameter can be controlled by the drawing ofthe polymer film as it exits the die. For a die having a diametersimilar to the target diameter, the axial draw down ratio can be between1 and 3. The axial drawdown ratio is defined as:

$\frac{{Drawn}\mspace{14mu}{Length}\mspace{14mu}{of}\mspace{14mu}{Tube}}{{Original}\mspace{14mu}{Length}\mspace{14mu}{of}\mspace{14mu}{Tube}}$

In further embodiments, it may be desirable to control the degree ofcrystallinity in a polymer tube during extrusion, radial deformation,and/or axial deformation to reduce or eliminate physical aging, creep,and stress relaxation in a stent. Additionally, it is also desirable tocontrol crystallinity to increase the toughness of a stent.

As discussed above, physical aging, creep, and stress relaxation are dueat least in part to rearrangement of polymer chains in amorphous regionsof a polymer. Thus, as crystallinity increases in a polymer, physicalaging, creep, and stress relaxation tend to reduce. Therefore, it isadvantageous to use crystalline or semi-crystalline polymers for a stentto reduce or eliminate physical aging, creep, and stress relaxation.

However, crystalline and semi-crystalline polymers can be relativelybrittle at biological conditions, i.e., the temperature of the humanbody. In particular, such polymers can have a Tg below the bodytemperature. These polymers can have a low fracture toughness and arethus susceptible to mechanical failure during use, for example, duringcrimping, deployment, and treatment. It is important for a stent to havea high fracture toughness throughout the range of stress experiencedduring use. For a semi-crystalline polymer, if the crystallinity is toohigh, example 50-60%, it is more likely that the polymer will be brittleunder biological conditions.

Semi-crystalline polymers can contain both amorphous and crystallinedomains at temperatures below their melting point. Amorphous regions arethose in which polymer chains are in relatively disorderedconfigurations. Crystalline domains are those in which polymer chainsare in ordered configurations with segments of polymer chainsessentially parallel to one another.

In certain embodiments, the crystallinity of an extruded tube, which ismade from a polymeric material and a nucleating agent, can be controlledby controlling the temperature of cooling the annular film exiting thedie. In general, crystallization tends to occur in a polymer attemperatures between Tg and Tm of the polymer. The rate ofcrystallization in this range varies with temperature. FIG. 7 depicts aschematic plot of the crystal nucleation rate (R_(N)), the crystalgrowth rate (R_(CG)), and the overall rate of crystallization (R_(CO)).The crystal nucleation rate is the growth rate of new crystals and thecrystal growth rate is the rate of growth of formed crystals. Theoverall rate of crystallization is the sum of curves R_(N) and R_(CG).

In certain embodiments, the temperature of the annular tube exiting theextruder during cooling can be at a temperature in a range in which thecrystal nucleation rate is larger than the crystal growth rate. In oneembodiment, the temperature can be in a range in which the crystalnucleation rate is substantially larger than the crystal growth rate.For example, the temperature can be where the ratio of the crystalnucleation rate to crystal growth rate is 2, 5, 10, or greater than 10.In another embodiment, the temperature range may be in range, ΔT shownin FIG. 7, between about Tg to about 0.5(Tm−Tg)+Tg.

Additionally, crystallinity in a polymeric tube can also be controlledduring radial deformation to increase fracture toughness and reducephysical aging, creep, and stress relaxation. As indicated above, it isdesirable to radially deform at a temperature above a Tg of the polymerto facilitate deformation and to heat set the polymer above the Tg. As aresult, crystallization tends to occur in the polymer during deformationand heat setting. In addition, crystallinity in addition to orientationmay be induced in the polymer during deformation. This process isreferred to as strain-induced crystallization.

Thus, embodiments of the method can include radially deforming and/orheat setting in temperature ranges described above for extrusion.Deforming and heat setting a tube in such a temperature range can resultin a radially deformed tube with a higher fracture toughness and reducedphysical aging, creep, and stress relaxation for the same reasons asexplained above for extrusion.

In other embodiments, an extruded tube can be formed that is amorphousor substantially amorphous. An amorphous polymeric tube can be formed byquickly quenching the annular tube exiting the die so that itstemperature is reduced to a temperature from above Tm to below Tg sothat very little or substantially no crystallization occurs in thepolymer during cooling. Thus, an amorphous glassy polymer can be formed.Then, to increase the crystallization, the tube can then be deformed andheat set, as described above, at a temperature that results in highfracture toughness and with reduced physical aging, creep, and stressrelaxation.

Polymers can be biostable, bioabsorbable, biodegradable or bioerodable.Biostable refers to polymers that are not biodegradable. The termsbiodegradable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded when exposed to bodily fluids such as blood and can begradually resorbed, absorbed, and/or eliminated by the body. Theprocesses of breaking down and eventual absorption and elimination ofthe polymer can be caused by, for example, hydrolysis, metabolicprocesses, bulk or surface erosion, and the like.

It is understood that after the process of degradation, erosion,absorption, and/or resorption has been completed, no part of the stentwill remain or in the case of coating applications on a biostablescaffolding, no polymer will remain on the device. In some embodiments,very negligible traces or residue may be left behind. For stents madefrom a biodegradable polymer, the stent is intended to remain in thebody for a duration of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished.

Representative examples of polymers that may be used to fabricate orcoat an implantable medical device include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),poly(caprolactone), poly(lactide-co-caprolactone), poly(trimethylenecarbonate), poly(lactide-co-trimethylene carbonate), polyester amide,poly(glycolic acid-co-trimethylene carbonate),poly(lactide-co-p-dioxanone), co-poly(ether-esters) (e.g. PEO/PLA),polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers other than polyacrylates,vinyl halide polymers and copolymers (such as polyvinyl chloride),polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidenehalides (such as polyvinylidene chloride), polyacrylonitrile, polyvinylketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters(such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABSresins, polyamides (such as Nylon 66 and polycaprolactam),polycarbonates, polyoxymethylenes, polyimides, polyethers,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose. Another type of polymer based on poly(lactic acid) that canbe used includes graft copolymers, and block copolymers, such as ABblock-copolymers (“diblock-copolymers”) or ABA block-copolymers(“triblock-copolymers”), or mixtures thereof.

Additional representative examples of polymers that may be especiallywell suited for use in fabricating or coating an implantable medicaldevice include ethylene vinyl alcohol copolymer (commonly known by thegeneric name EVOH or by the trade name EVAL), poly(butyl methacrylate),poly(vinylidene fluoride-co-hexafluororpropene) (e.g., SOLEF 21508,available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidenefluoride (otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

The embodiments which include a nucleating agent can be used with any ofthese aforementioned polymers.

EXAMPLES

The examples and experimental data set forth below are for illustrativepurposes only and are in no way meant to limit the invention. Thefollowing examples are given to aid in understanding the invention, butit is to be understood that the invention is not limited to theparticular materials or procedures of examples.

Example 1 PLGA Stent Preparation Using PGA as a Nucleating Agent

-   1. Blend Preparation—1 kg of high molecular weight PLGA    (LLA:GA=90:10) is blended with 50 g PGA at room temperature in a    mechanical blender, or through melt blending using a twin screw    extruder, or through solution blending by dissolving both PLGA and    PGA in a co-solvent and precipitating them in a non-solvent.-   2. Tubing Extrusion—The PLGA tubing is formed through extrusion in a    single or twin screw extruder with a puller. The size of the    extruded tubing is set at 0.02″ for the ID and 0.07″ for the OD. The    tubing is cooled to room temperature.-   3. Stent Preparation—In order to further increase the crystallinity    of the extruded PLGA tubing, the tubing with ID=0.02″ and OD=0.07″    is expanded in a glass mold at about 180° F. The tubing is then    cooled to room temperature. The expanded tubing has an ID=0.12″ and    an OD=0.13″ and is cut by a laser and crimped to a smaller size of    0.05″.

Example 2 PLGA Stent Preparation Using PGLA as a Nucleating Agent

-   1. Blend Preparation—1 kg of high molecular weight PLGA    (LLA:GA=90:10) is blended with 50 g PGLA (GA:LLA=98:2) at room    temperature in a mechanical blender, or through melt blending using    a twin screw extruder, or through solution blending by dissolving    both PLGA and PGLA in a co-solvent and precipitating them in a    non-solvent.-   2. Tubing Extrusion—The PLGA tubing is formed through extrusion in a    single or twin screw extruder with a puller. The size of the    extruded tubing is set at 0.02″ for the ID and 0.07″ for the OD. The    tubing is cooled to room temperature.-   3. Stent Preparation—In order to further increase the crystallinity    of the extruded PLGA tubing, the tubing with ID=0.02″ and OD=0.07″    is expanded in a glass mold at about 180° F. The tubing is then    cooled to room temperature. The expanded tubing has an ID=0.12″ and    an OD=0.13″ and is cut by a laser and crimped to a smaller size of    0.05″.

Example 3 PLGA Stent Preparation Using Nano Magnesium Silicate Hydrateas a Nucleating Agent

-   1. Blend Preparation—1 kg of high molecular weight PLGA    (LLA:GA=90:10) is blended with 10 g nano magnesium silicate hydrate    at room temperature in a mechanical blender, or through melt    blending using a twin screw extruder, or through solution blending    by dissolving PLGA in a solvent with suspended nano magnesium    silicate hydrate particles and precipitating the mixture in a    non-solvent.-   2. Tubing Extrusion—The PLGA tubing is formed through extrusion in a    single or twin screw extruder. The size of the extruded tubing is    set at 0.02″ for the ID and 0.07″ for the OD. The tubing is cooled    to room temperature.-   3. Stent Preparation—In order to further increase the crystallinity    of the extruded PLGA tubing, the tubing with ID=0.02″ and OD=0.07″    is expanded in a glass mold at about 180° F. The tubing is then    cooled to room temperature. The expanded tubing has an ID=0.12″ and    an OD=0.13″ and is cut by a laser and crimped to a smaller size of    0.05″.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method for fabricating a polymeric stent comprising: combining a main polymer with a nucleating agent to form a polymer mixture, wherein the main polymer is poly(lactide-co-glycolide)(PLGA) with an L-lactide:glycolide ratio of 85:15 to 95:5, wherein the nucleating agent is poly(glycolide-co-lactide) with less than 10 wt % L-lactide, wherein the nucleating agent has a faster crystallization rate than the main polymer and a faster degradation rate than polyglycolide, wherein the nucleating agent is present in the range of 0.1 to 10% by weight of the polymer mixture; forming polymer tubing from the polymer mixture, wherein the nucleating agent increases crystallinity of the tubing; and fabricating the stent from the tubing.
 2. The method of claim 1, further comprising a stress inducing crystallization step, wherein the nucleating agent enhances the crystallization during the stress induced crystallization step.
 3. The method of claim 2, wherein the stress inducing crystallization step also decreases crystal size.
 4. The method of claim 2, wherein the stress inducing crystallization step includes deformation of the polymer tubing radially, axially, or both before fabricating the stent from the deformed tubing.
 5. The method of claim 2, wherein the stress inducing crystallization step is carried out before fabricating the stent by radially deforming the formed polymer tubing for fabricating a stent from the deformed polymer tubing, wherein heating of the polymer tubing and increasing an internal tubing pressure higher than ambient facilitates the radial deforming.
 6. The method of claim 2, wherein the stress inducing crystallization step includes axial deformation using blow molding and by applying a tensile force by a tension source to at least one end of the polymer tubing.
 7. The method of claim 6, wherein the stress inducing crystallization step comprises applying a tensile force at both ends of the polymer tubing.
 8. The method of claim 2, wherein the stress inducing crystallization step comprises heat setting the polymer tubing at a temperature above Tg.
 9. The method of claim 1, wherein the nucleating agent is present in the range of 0.2 to 5% by weight of the polymer mixture.
 10. The method of claim 1, wherein the main polymer and the nucleating agent are combined by solution blending, the solution blending comprising dissolving the PLGA and the nucleating agent in a co-solvent and precipitating the PLGA and nucleating agent to form the mixture. 